Endothelial damage occurs early in the development of a coronary atherosclerotic plaque. Moreover, following angioplasty and stenting, there is significant injury to the arterial wall, with loss of endothelial coverage. Gradual re-endothelialization of the stented segment occurs, but this process is significantly delayed with drug eluting stents, and is a major mechanistic contributor to stent thrombosis. Joner et al., “Endothelial cell recovery between comparator polymer-based drug-eluting stents” J Am Coll Cardiol. 52:333-3342 (2008); and Finn et al., “Vascular responses to drug eluting stents: importance of delayed healing” Arterioscler Thromb Vasc Biol. 27:1500-1510 (2007), respectively.
Very few drugs and other biologicals such as hormones and/or biopeptides have successfully improved tissue regeneration and/or healing. For the most part, most drugs involve indirect mechanisms such as reducing inflammation. Furthermore, compounds having a significant direct effect stimulating cell proliferation are not yet approved for clinical use.
Since the first coronary percutaneous intervention (PCI) performed by Dr. Andreas Grunzing in 1977, the field of interventional cardiology has progressed exponentially, with a major impact in the treatment and outcome of coronary artery disease (CAD). The technology for treating atherosclerotic plaque has progressed from simple balloon angioplasty to intracoronary placement of bare metal stents (BMS) and more recently, to the usage of drug eluting stents (DES), which have been effective at preventing in-stent restenosis associated with BMS. However, one of the problems emerging with the widespread clinical application of stents, in particular with DES, is the occurrence of stent thrombosis, sometimes occurring very late following the index procedure, with devastating clinical consequences. Lagerqvist et al., “SCAAR Study Group. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden” N Engl J Med. 356(10):1009-1019 (2007). It has been reported that up to 7% of acute myocardial infarctions (MI) are caused by stent thrombosis. Browning et al., “The changing face of ST Elevation myocardial infarction; trends in the drug eluting stent era” Catheter Cardiovasc Intervention 73:11 (2009). Stent thrombosis occurs at a rate of 0.25-0.5% yearly with DES, and it is unclear whether a plateau has been reached yet. Pfiesterer et al., “Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents” J Am Coll Cardiol 48:2584-2591 (2006). Hence, with nearly a million coronary stents implanted yearly in the United States alone, the incidence of MI due to stent thrombosis is a potentially expanding problem.
The failure of the normal protective functions of the vascular endothelium is the hallmark of atherosclerotic cardiovascular disease, leading to the formation of atherosclerotic plaques as well as insufficient repair of sites of arterial injury. A similar problem occurs with the use of arterial stents, with late thrombosis due to delayed healing of the vessel wall and incomplete endothelial coverage of the stents struts as well as other artificial vascular prostheses. Takano et al., “Serial long-term evaluation of neointimal stent coverage and thrombus after sirolimus-eluting stent implantation by use of coronary angioscopy” Heart 93(11):1353-1356 (2007),
What is needed in the art are compositions and methods that can be delivered locally and are capable of accelerating biological pathways (i.e., for example, cell proliferation) where systemically delivered drugs and/or biological compounds are not available and/or marginally clinically effective.